Pharmacotherapy of Invasive Fungal Infections with Voriconazole

Abstract

Voriconazole, a second-generation and broad-spectrum triazole derivative of fluconazole, inhibits the cytochrome P450 (CYP)-dependent enzyme 14-α-sterol demethylase, which is a pivotal step in cell membrane ergosterol synthesis in fungi. CYP2C19, CYP3A4, flavin-containing monooxygenase (FMO), and to a lesser extent CYP2C9 contribute to the oxidative metabolism of voriconazole by human liver microsomes. Clinical trials have demonstrated the safety and efficacy of voriconazole for prophylaxis and treatment in candidiasis, invasive aspergillosis, and in invasive fungal infections (IFIs) caused by a variety of non-Aspergillus molds, such as Fusarium or Scedosporium spp., and was generally well tolerated as primary therapy in adults and children. The availability of both parenteral and oral formulations and the nearly complete absorption (bioavailability of 96% for adults, ca. 40% in children) of the drug after oral administration provide for ease of use and potential cost savings, and ensure that the therapeutic plasma concentrations are maintained when switching from intravenous to oral regimes. It exhibits nonlinear pharmacokinetics in healthy controls and patients at high risk of IFIs, but considerable intra- and interpatient pharmacokinetic variability has raised the question of therapeutic drug monitoring. Most common adverse events are visual disturbances and elevated transaminase levels. The emergence of resistance towards voriconazole has been rarely reported.